Antibodies were determined against five synthetic peptides (epitopes) of HIV-1 p17 in the sera of an immunologically and clinically well-characterized cohort (N = 292) of HIV-1 seronegative and HIV-1 seropositive high-risk homosexual men, HIV-1 seropositive i.v. drug abusers (IVDA), and AIDS patients. The synthetic peptides, representing the entire HIV-1 p17 protein sequence were: HGP-33 (aa 1–33), HGP-19 (aa 34–52), HGP-35 (aa 51–85), HGP-30 (aa 85–114), and HGP-17 ala (aa 114–131). The presence of one or more peptide-specific antibodies in the sera of all of the HIV-1 p17-positive subjects indicated that all five peptides contain B-cell epitopes. No antibodies were found in the sera of heterosexual controls, HIV-1 seronegative high-risk men, or asymptomatic HIV-1 seropositive but p17 antibody-negative study subjects. Significant differences in antibody recognition profiles to the peptide epitopes were found among the various study groups. A significantly higher proportion of HIV-1 seropositive IVDA had antibodies specific to HGP-17 ala (aa 114–131), HGP-35 (aa 51–85), and HGP-33 (aa 1–33) compared to the HIV-1 p17-positive asymptomatic homosexuals. The epitope-specific antibody responses reflected the clinical status of the HIV-1-infected study subjects, and declined to nondetectable levels as the patient progressed to ARC/AIDS. This decline preceded by several months the reduction in the antibody titer against the intact HIV-1 p17 and p24 proteins. Thus, the antibody response against specific HIV-1 p17 epitopes might be a better prognostic indicator than the total antibody response against the native HIV-1 p17 protein.